Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of community-acquired pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumonia, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.
CAP remains a significant health problem and patients continue to die despite receiving appropriate antibiotic therapy. Modification of the host immune response, both anti- and pro-inflammatory approaches, has yet to live up to the promise of improved outcome. Despite this, there is significant reason for optimism. Some immunomodulatory therapies clearly have efficacy in some patients. As the understanding of the immune response to pneumonia improves the ability to tailor specific therapies for individual patients will also improve, hopefully avoiding the deleterious effects that have so far prevented the development of an effective immune based therapy. The possibility of delivering cytokines directly to the lung, is a particularly promising way of achieving the desired pulmonary effect without systemic side effects. Corticosteroids are currently unique in that they have a proven role in the therapy of pneumonia due to P. carinii. The development of pathogen specific therapies, such as INF for L. pneumophila, based on an improved understanding of host-pathogen interactions, are awaited.
The past 20 years has seen an explosion in our knowledge of human immunology and we are only now beginning to explore the therapeutic possibilities this has made available. The next 10 years promises to finally provide a significant advance in the therapy of pneumonia, the first substantial gain since penicillin.
In light of the prevalence of CAP and the evolution of resistance in the most common bacterial CAP pathogen, physicians advise obtaining specimens for culture of CAP pathogens and analyzing patterns of susceptibility, especially of S. pneumonia, in their communities, using antibiotics appropriately and prudently, according to prevailing susceptibilities when empirical treatment is called for, and immunizing susceptible patients with pneumococcal and influenza vaccines. This is because the mortality of patients with severe CAP approaches or may exceed 20%, compared to less than 1% for patients with non-severe CAP (Fine et al. New Engl. J. Med. 1997.336:243-238, British Thoracic Society, Q. J. Med. 1987.239:192-220, Niederman et al. Am. Rev. Resp. Dis. 1993.148:1418-1426). In such cases an ability to improve accuracy of diagnosis of, or predisposition or susceptibility to, severe CAP would be of distinct advantage and may lead to improved outcomes and lower medical costs for such patients.
TNF.alpha. acts on many healthy cells in addition to cancer cells and has been widely described in the literature. See e.g., Alfonso et al. Immunogenetics 1994.39:150-154. It is important in regulating immune and inflammatory responses and plays a large role in septic shock. It is released by a variety of cells including red and white blood cells, cells that line blood vessels, nervous system cells, muscle cells, bone cells, and some tumor cells. Although it was first observed to kill certain tumor cells (sarcoma cells), TNF has been found to help some tumors grow. In addition, TNF can be very toxic to normal cells. Early experiments found that administering TNF caused fever and loss of appetite. TNF also has been shown to affect the metabolism of many cell types, causing them to need more oxygen. It has been found to play a role in many autoimmune diseases, such as rheumatoid arthritis and myasthenia gravis. Certain viral and bacterial infections can cause healthy cells to produce elevated levels of TNF.
Tumor necrosis factor alpha (TNF.alpha.) is a critical component of the host immune response to infection. However TNF.alpha. also plays a major role in the clinical manifestations of septic shock, a frequently fatal complication of CAP. A number of polymorphisms in or near the TNF.alpha. gene on chromosome 6 have been described. The TNF.alpha. -238 polymorphism is a guanine (G) to adenine (A) transition, with the A allele associated with greater TNF.alpha. production in-vitro, although this has not been a uniform finding. Carriage of the TNF.alpha.-238 A allele has been associated with an increased risk of severe malarial anemia, chronic hepatitis B and C infection, alcoholic steatohepatitis, and psoriasis.
Carriage of the A allele of the TNF.alpha.-238 polymorphism is believed to be associated with a greater risk of mortality, and greater risk of septic shock, in patients with CAP. It is a surprising feature of the present invention to be able to identify patients having an increased risk of death from CAP by the method of the present invention thereby identifying more effective treatment options such as pneumococcal and influenza vaccination of such at risk patients.